POS1266 A PHASE IA, RANDOMIZED STUDY TO EVALUATE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF SINGLE ASCENDING DOSES OF RO7303509, AN ANTI-TGFΒ3 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS
Authors: L. Han, S. Jamalian, L. Pan, X. R. Sheng, X. Yang, X. Yang, S. Hassan, S. Monemi, A. Stillwell, S. Glickstein, R. Kunder
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis.<sup>[1]</sup> However, treating fibrotic diseases with systemic pan-TGFβ inhibitors has demonstrated unacceptable toxicities.<sup>[2,3]</sup> In human lung and liver fibrotic tissue, and in the skin of patients with systemic sclerosis, elevated <i>TGFB3</i> gene expression suggests its use as a more specific therapeutic target.<sup>[2,4]</sup> RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 (IgG1) monoclonal antibody, is being developed as a potential anti-fibrotic therapy. <h3>Objectives</h3> To evaluate RO7303509 safety, tolerability, pharmacokinetics, and pharmacodynamics. <h3>Methods</h3> This phase 1a, randomized, double-blind trial (ISRCTN13175485) in healthy adult volunteers (HVs) consisted of 6 cohorts that evaluated single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The follow-up period was 12 weeks. Throughout the study, we monitored frequency and severity of adverse events (AEs) and RO7303509 plasma concentrations. We also measured TGFβ pathway biomarkers, including serum periostin and cartilage oligomeric matrix protein (COMP), by immunoassay. <h3>Results</h3> The study enrolled 49 HVs, 18–73 years old, with a median baseline weight of 79 kg. Twenty-seven subjects (55%) were male; 8 (16%) were Black or African American, 1 (2%) was Asian, 1 (2%) was multiracial, and 39 (80%) were White; 1 (2%) was Hispanic or Latino. Ten (28%) RO7303509-treated subjects reported 24 AEs, and 6 (31%) placebo-treated subjects reported 6 AEs. All AEs were Grade 1 except for one Grade 2 AE of hyperamylasemia (unrelated) in the 1200-mg SC cohort. The most frequent AEs related to study drug were injection site reactions (1200 mg SC: 4 RO7303509, 1 placebo) and infusion-related reactions (240 mg IV: 1 RO7303509, 2 placebo). Median times to maximum plasma concentration (T<sub>max</sub>) of RO7303509 after single IV and SC doses were 1–2 hours and 5–7 days, respectively. Geometric mean plasma half-lives (t<sub>1/2</sub>) for IV and SC dosing were ~23 days. Maximum plasma concentrations (C<sub>max</sub>) and area under the curve from time 0 to infinity (AUC<sub>0-inf</sub>) values for RO7303509 appeared to increase proportionally across all doses tested after adjusting for the observed subcutaneous bioavailability of 73%. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; 1 subject (2.8%; 50 mg IV) tested positive for ADAs at a single timepoint (Day 15). No clear pharmacodynamic effects were observed for the biomarkers periostin or COMP upon TGFβ3 inhibition. <h3>Conclusion</h3> RO7303509 was well tolerated at single IV and SC doses up to 1200 mg without any dose-limiting toxicities, Grade ≥3 AEs, serious AEs, deaths, or clinically significant vitals/ ECG changes. In addition to a favorable safety profile, the dose-proportional increase in RO7303509 exposure across the dose range after single dose administration supports further development using repeat-dosing regimens. The half-life supports SC administration every four weeks. The lack of an effect on TGFβ pathway biomarkers likely indicates that TGFβ3 is inactive during homeostasis, which suggests that targeting this pathway may have a favorable safety profile. These data support the further development of RO7303509 for the treatment of fibrotic diseases. <h3>References</h3> [1]Morikawa M, et al. Cold Spring Harb Perspect Biol 2016;8:a021873. [2]Sun T, et al. Sci Transl Med 2021;13(605):eabe0407. [3]Rice LM, et al. J Clin Invest 2015;125:2795−807. [4]Kaundal U et al. Arthritis Rheumatol 2022; 74 (suppl 9). <h3>Acknowledgements</h3> We would like to thank all the volunteers who participated and all of the clinical site staff who assisted with this trial. <h3>Disclosure of Interests</h3> Lyrialle Han Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Samira Jamalian Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Lin Pan Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, X. Rebecca Sheng Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Xiaoyun Yang Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Xiaoying Yang Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Sharmeen Hassan Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Sharareh Monemi Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Allayah Stillwell Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Sara Glickstein Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group, Rebecca Kunder Shareholder of: Roche, Employee of: Genentech, Inc., a member of the Roche group.